Background:
Charcot-Marie-Tooth disease Type 2S (CMT2S) is a rare subtype of Charcot-Marie-Tooth disease caused by pathogenic variants in the IGHMBP2 gene, which result in abnormal RNA processing and lead to alpha‐motor neuron degeneration. We evaluated a case of CMT2S caused by two IGHMBP2 variants: a pathogenic missense variant acting in trans with a confirmed intronic cryptic splice site variant (c.1235+894 C>A) deep in intron 8. We developed an ASO, VCA-894A, that targets this variant to restore canonical splicing, rescuing IGHMBP2 levels. We report the first doses in the first-in-human clinical trial to evaluate the safety and tolerability of VCA-894A.
Objectives:
VCA-894A is being assessed in an ‘N of 1’, open-label, single center study to evaluate the safety of therapy when administered by intrathecal injection. The primary objectives of the clinical trial are to evaluate the safety of therapy with VCA-894A when administered via intrathecal injection, and to determine whether the chronic administration of intrathecal VCA-894A can reduce or stabilize the symptoms of CMT2S. Additional exploratory endpoints study the degree of on target engagement via boosting IGHMBP2 expression levels as well as reducing pNFL levels.
Results:
In patient fibroblasts, treatment with VCA-894A significantly increased the ratio of restored WT transcript to cryptic exon containing transcript, resulting in over a 50% increase in IGHMBP2 protein levels. Following treatment with VCA-894A, we demonstrate rescue of NMJ functioning, captured by a decrease in FI and decay and chaotic responses. Following ASO treatment, CMT2S-MNs experienced a significant dose-dependent rescue of CV and number of conductions, compared to WT-MNs and vehicle treated CMT2S-MNs.
Following this, a clinical study has been initiated and upon several escalations, a dose of 12 mg has been reached. Early results are pointing to an on-target engagement with significant increase in IGHMBP2 expression as captured by qPCR analysis as well as ELISA. Importantly, a significant reduction in Phosphorylated Neurofilament Heavy Chain (pNfH) has been observed upon recurrent dosing. The study is ongoing.
Conclusions:
N-of-1 ASO-based therapeutics may prove instrumental in the design of treatments for this diverse genetic disorder. Ever since the study has been made public additional splicing variants in the same gene ‘hotspot’ have been delineated.